BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways

Author:

de Jesus Perez Vinicio A.1,Ali Ziad1,Alastalo Tero-Pekka1,Ikeno Fumiaki1,Sawada Hirofumi1,Lai Ying-Ju1,Kleisli Thomas1,Spiekerkoetter Edda1,Qu Xiumei1,Rubinos Laura H.2,Ashley Euan1,Amieva Manuel1,Dedhar Shoukat3,Rabinovitch Marlene1

Affiliation:

1. Department of Medicine and Department of Pediatrics, Stanford University, Stanford, CA 94305

2. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030

3. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Abstract

We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)–β-catenin (βC) and Wnt–planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt–dependent manner, induces βC transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via α4-integrins. ILK-1 then induces the Wnt–PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1–mediated motility. Transfection of a Dvl mutant that binds βC without activating RhoA-Rac1 not only prevents BMP-2–mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent βC activity. Interfering with the Dvl-dependent Wnt–PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2–mediated tandem activation of Wnt–βC and Wnt–PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.

Publisher

Rockefeller University Press

Subject

Cell Biology

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